Ciprofloxacin - instructions for use, dose, side effects, contraindications

Active substance:
Ciprofloxacin hydrochloride	111.0 mg
in terms of ciprofloxacin	100.0 mg
Excipients:
Lactic acid	37.2 mg
Disodium edetate dihydrate	1.0 mg
Sodium hydroxide *	q.s.
Hydrochloric acid *	q.s.
Water for injections	up to 10 ml

* Used when necessary in the process to adjust the pH value from 3.3 to 3.9.

Description:

Transparent, colorless or slightly yellow-green solution.

Pharmacotherapeutic group:antimicrobial agent - fluoroquinolone

ATX: & nbsp

J.01.M.A.02 Ciprofloxacin

Pharmacodynamics:

Ciprofloxacin is a synthetic antibacterial agent of a broad spectrum of action from the group of fluoroquinolones.

Mechanism of action

Ciprofloxacin has activity in vitro for a wide range of gram-negative and gram-positive microorganisms. The bactericidal action of ciprofloxacin is effected by inhibiting bacterial topoisomerases II (topoisomerase II (DNA gyrase) and topoisomerase IV), which are necessary for replication, transcription, repair and recombination of bacterial DNA.

Mechanisms of resistance

Resistance in vitro to ciprofloxacin is often caused by point mutations of bacterial topoisomerases and DNA gyrase and develops slowly, through multistage mutations.

Single mutations can lead to a decrease in sensitivity rather than to the development of clinical stability, but multiple mutations mainly lead to the development of clinical resistance to ciprofloxacin and to cross-resistance to quinolone drugs.

Resistance to ciprofloxacin, as well as to many other antibiotics, can be formed as a result of a decrease in the permeability of the bacterial cell wall (as is often the case with Pseudomonas aeruginosa) and / or activation of excretion from the microbial cell (efflux). The development of resistance due to the encoding gene localized on plasmids has been reported Qnr. Resistance mechanisms that lead to the inactivation of penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines probably do not interfere with the antibacterial activity of ciprofloxacin. Microorganisms resistant to these drugs may be sensitive to ciprofloxacin.

The minimum bactericidal concentration (MBC) usually does not exceed the minimum inhibitory concentration (MIC) by more than 2 times.

Sensitivity testing in vitro

Reproducible criteria for testing susceptibility to ciprofloxacin approved by the European Committee for the Determination of Sensitivity to Antibiotics (EUCAST) are presented in the table below.

Boundary MIC values (mg / L) in clinical settings for ciprofloxacin (European Committee for the Determination of Antibiotic Sensitivity)

Microorganism	Sensitive	Resistant
Enterobacteriaceae	≤0,5	>1
Pseudomonas spp.	≤0,5	>1
Acinetobacter spp.	<1	>1
Staphylococcus¹ spp.	≤1	>1
Streptococcus pneumoniae²	≤0,125	>2
Haemophilus influenzae and Moraxella catarrhalis³	≤0,5	>0,5
Neisseria gonorrhoeae Neisseria meningitidis	≤0,03	>0,06
Boundary values not associated with microbial species⁴	≤0,5	>1

¹ Staphylococcus spp.: borderline values for ciprofloxacin and ofloxacin are associated with high-dosage therapy.

² Streptococcus pneumoniae: wild type S. pneumoniae is not considered sensitive to ciprofloxacin and thus belongs to the category of microorganisms with intermediate sensitivity.

³ Strains with a MIC value greater than the threshold sensitivity / moderately sensitive thresholds are very rare, and so far there have been no reports of them.Tests for identification and antimicrobial sensitivity in the detection of such colonies must be repeated, and the results should be confirmed when analyzing the colonies in the reference laboratory. Until the evidence of a clinical response is obtained for strains with confirmed MIC values exceeding the current resistance threshold, they should be considered as resistant. Haemophilus spp. / Moraxella spp.: it is possible to identify strains H. influenzae with a low sensitivity to fluoroquinolones (MIC for ciprofloxacin - 0.125-0.5 mg / l). Evidence of the clinical significance of low resistance in respiratory infections caused by H. influenzae, no.

⁴ Boundary values not associated with microbial species were determined mainly on the basis of pharmacokinetics / pharmacodynamics data and are not dependent on MIC distribution for specific species. They are applicable only to species for which a sensitivity threshold specific to the species has not been determined, and not for those for which testing of sensitivity is not recommended. For certain strains, the spread of acquired resistance may vary depending on the geographical region and over time.In this regard, it is desirable to have local information on resistance, especially when treating serious infections.

Data from the Institute of Clinical and Laboratory Standards for MIC boundary values (mg / L) and diffusion testing (zone diameter [mm]) using discs containing 5 μg of ciprofloxacin are presented in the table below.

Boundary MIC values (mg / L) and diffusion testing (mm) using discs (Institute of Clinical and Laboratory Standards)

Microorganism	Sensitive	Intermediate	Resistant
Enterobacteriaceae	<1¹	2¹	>4¹
Enterobacteriaceae	>21²	16-20²	<15²
Enterococcus spp.	1¹	2¹	>4¹
Enterococcus spp.	>21²	16-20²	<15²
Haemophilus spp.	<1³	-	-
Haemophilus spp.	>21⁴	-	-
Neisseria gonorrhoeae	<0,06⁵	0,12-0,5⁵	>1⁵
Neisseria gonorrhoeae	>41⁵	28-40⁵	<27₅
Neisseria meningitidis	<0,03⁶	0,06⁶	>0,12⁶
Neisseria meningitidis	>35⁷	33-34⁷	<32⁷
Bacillus anthracis Yersinia pestis	<0,25¹	-	-
Francisella tularensis	<0,5³	-	-

¹This reproducible standard is applicable only to dilutions with broth using cationic corrected Mueller-Hinton broth (SAMS) which is incubated with air access at a temperature of 35 ± 2 ° C for 16-20 h for strains Enterobacteriaceae, Pseudomonas aeruginosa, other bacteria not belonging to the Enterobacteriaceae family, Staphylococcus spp., Enterococcus spp. and Bacillus anthracis; 20-24 hours for Acinetobacter spp., 24 h for Y. pestis (with insufficient growth, incubate for another 24 hours).

² This reproducible standard is applicable only to diffusion tests using Müller-Hinton agar plates that are incubated with air access at a temperature of 35 ± 2 ° C for 16-18 hours.

³ This reproducible standard is applicable only to diffusion tests using discs to determine sensitivity to Haemophilus influenzae and Haemophilus parainfluenzae using a broth test medium for Haemophilus spp. (NTM), which is incubated with air access at a temperature of 35 ± 2 ° C for 20-24 hours.

⁴ This reproducible standard is applicable only to diffusion tests using discs using an NTM test medium which is incubated in a 5% CO₂ at a temperature of 35 ± 2 ° C for 16-18 hours.

⁵ This reproducible standard is applicable only to sensitivity tests (diffusion tests using zone discs and agar agar for MIC) using gonococcal agar and 1% of the growth additive at 36 ± 1 ° C (not exceeding 37 ° C) in 5% CO₂ for 20-24 hours.

⁶ This reproducible standard is applicable only to dilution tests with broth using cationic corrected Mueller-Hinton broth (SAMS) supplemented with 5% sheep blood which is incubated in 5% CO₂ at 35 ± 2 ° C for 20-24 hours.

⁷ This reproducible standard is applicable only to tests using cationic corrected Mueller-Hinton broth (SAMS) with the addition of a specific 2% growth additive,which is incubated with air access at 35 ± 2 ° C for 48 hours.

In vitro sensitivity to ciprofloxacin

For certain strains, the spread of acquired resistance may vary depending on the geographical region and over time. In this regard, when testing the sensitivity of a strain, it is desirable to have local information on resistance, especially when treating severe infections. If the local prevalence of resistance is such that the use of the drug, at least for several types of infections, is questionable, it is necessary to consult a specialist.

In vitro the activity of ciprofloxacin in relation to the following sensitive strains of microorganisms was demonstrated:

Aerobic Gram-positive microorganisms: Bacillus anthracis, Staphylococcus aureus (methicillin-sensitive), Staphylococcus saprophyticus, Streptococcus spp.

Aerobic Gram-negative microorganisms: Aeromonas spp., Moraxella catarrhal is, Brucella spp., Neisseria meningitidis, Citrobacter koseri, Pasteurella spp., Francisella tularensis, Salmonella spp., Haemophilus ducreyi, Shigella spp., Haemophilus influenzae, Vibrio spp., Legionella spp., Yersinia pestis.

Anaerobic microorganisms: Mobiluncus spp.

Other microorganisms: Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma hominis, Mycoplasma pneumoniae.

A varying degree of sensitivity to ciprofloxacin for the following microorganisms was demonstrated: Acinetobacter baumanii, Burkholderia cepacia, Campylobacter spp., Citrobacter freundii, Enterococcus faecalis, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Providencia spp., Pseudomonas aeruginosa, Pseudomonas fluorescens, Serratia marcescens, Streptococcus pneumoniae, Peptostreptococcus spp., Propionibacterium acnes.

It is believed that the natural resistance to ciprofloxacin possess Staphylococcus aureus (methicillin-resistant), Stenotrophomonas maltophilia, Actinomyces spp., Enterococcus faecium, Listeria monocytogenes, Mycoplasma genitalium, Ureaplasma urealyticum, anaerobic microorganisms (with the exception of Mobiluncus spp., Peptostreptococcus spp., Propionibacterium acnes).

Pharmacokinetics:

Suction

After intravenous (iv) administration, the maximum concentration of ciprofloxacin in the blood plasma (FROM_mOh) is achieved at the end of the infusion. With intravenous administration, the pharmacokinetics of ciprofloxacin was linear in the dosage range up to 400 mg.

With intravenous administration of the drug 2 or 3 times a day, no cumulation of ciprofloxacin and its metabolites.

Distribution

The relationship of ciprofloxacin with plasma proteins is 20-30%. The active substance is present in the blood plasma mainly in non-ionized form. Ciprofloxacin freely distributed in tissues and body fluids. The volume of distribution in the body is 2-3 l / kg. The concentration of ciprofloxacin in tissues is much higher than the concentration in serum.

Metabolism

Ciprofloxacin is biotransformed in the liver. In the blood, 4 metabolites of ciprofloxacin can be detected in small concentrations: diethylciprofloxacin (M1), sulphociprofloxacin (M2), oxocycrofloxacin (M3), formyl ciprofloxacin (M4), 3 of which (Ml-M3) show antibacterial activity in vitro, comparable with antibacterial activity nalidixic acid. Antibacterial activity in vitro metabolite M4, present in a smaller amount, more corresponds to the activity of norfloxacin.

Excretion

Ciprofloxacin is excreted from the body mainly by the kidneys through glomerular filtration and tubular secretion; a small amount - through the gastrointestinal tract. The renal clearance is 0.18-0.3 l / h / kg, the total clearance is 0.48-0.60 l / h / kg. Approximately 1% The administered dose is excreted with bile. In the bile ciprofloxacin is present in high concentrations. In patients with unchanged renal function, the half-life period is usually 3-5 hours. If the renal function is impaired, the elimination half-life increases.

Children

In a study in children, the value of C_mOh and the area under the "concentration-time" curve (AUC) did not depend on age. A marked increase in C_mOh and AUC with repeated use of the drug (at a dose of 10 mg / kg 3 times a day) was not observed.In 10 children with severe sepsis less than 1 year of age FROM_m_Oh was 6.1 mg / L (range from 4.6 to 8.3 mg / L) after infusion for 1 hour at a dose of 10 mg / kg, and in children aged 1 to 5 years, 7.2 mg / l (range from 4.7 to 11.8 mg / l). Values AUC in the corresponding age groups were 17.4 (range from 11.8 to 32.0 mg / L) and 16.5 mg h / l (range from 11.0 to 23.8 mg h / l). These values correspond to the range reported to adult patients when therapeutic doses are administered. Based on pharmacokinetic analysis in children with various infections, the expected average half-life is approximately 4-5 hours.

Indications:

Uncomplicated and complicated infections caused by susceptible to ciprofloxacin microorganisms.

Adults

- respiratory tract infections. Ciprofloxacin recommended for pneumonia caused by Klebsiella spp., Enterobacter spp., Proteus spp., Escherichia coli, Pseudomonas aeruginosa, Haemophilus spp., Moraxella catarrhalis, Legionella spp. and Staphylococcus spp.;

- infections of the middle ear (otitis media), sinus congenital sinuses (sinusitis), especially if these infections are caused by gram-negative microorganisms, including Pseudomonas aeruginosa or Staphylococcus spp.;

- eye infections;

- infections of the kidneys and urinary tract;

- infection of the genitals, including adnexitis, gonorrhea, prostatitis;

- infection of the abdominal cavity (bacterial infections of the gastrointestinal tract, bile ducts, peritonitis);

- infections of the skin and soft tissues;

- sepsis;

- infection or prevention of infections in patients with reduced immunity (patients taking immunosuppressants or patients with neutropenia);

- selective decontamination of the intestine in patients with decreased immunity;

- prevention and treatment of pulmonary form of anthrax (infection Bacillus anthracis).

Children

- treatment of complications caused by Pseudomonas aeruginosa, in children from 5 to 17 years with cystic fibrosis of the lungs;

- prevention and treatment of pulmonary form of anthrax (infection Bacillus anthracis).

In connection with possible undesirable phenomena from the joints and / or surrounding tissues (see "Side effect"), treatment should begin with a doctor with experience in the treatment of severe infections in children and adolescents and after a thorough assessment of the relationship between benefit and risk.

In the case of mixed infections characterized by the presence of anaerobic microorganisms, ciprofloxacin It should be used in combination with other antibiotics that are effective against anaerobes.

It is important to follow the official guidelines for the proper use of antibacterial drugs.

Contraindications:

- Hypersensitivity to ciprofloxacin and other preparations of the fluoroquinolones group, as well as to the auxiliary substances included in the preparation;

- simultaneous reception with tizanidine (risk of pronounced reduction in blood pressure, drowsiness);

- pseudomembranous colitis;

- children under 18 years of age (before completion of the skeletal process, except for the treatment of complications caused by Pseudomonas aeruginosa, in children with cystic fibrosis of the lungs and prevention and treatment of the pulmonary form of anthrax);

- pregnancy;

- the period of breastfeeding.

Carefully:

Severe atherosclerosis of cerebral vessels, impaired cerebral circulation, increased risk of lengthening the interval QT or the development of piruet-type arrhythmias (eg, congenital lengthening syndrome QT, heart disease (heart failure, myocardial infarction, bradycardia), electrolyte imbalance (eg, hypokalemia, hypomagnesemia)), deficiency of glucose-6-phosphate dehydrogenase; simultaneous use of drugs that extend the interval QT (including antiarrhythmic drugs IA and III classes, tricyclic antidepressants, macrolides, neuroleptics), simultaneous application with inhibitors of isoenzymes CYP4501A2, including theophylline, methylxanthine, caffeine, duloxetine, clozapine, ropinirole, olanzapine (see section "Special instructions"); patients with a history of tendon damage associated with the use of quinolones, mental illness (depression, psychosis), central nervous system (CNS) diseases: epilepsy, lowering the threshold of convulsive readiness (or convulsive seizures in an anamnesis), organic brain damage or stroke; marked renal and / or liver failure; elderly age.

Pregnancy and lactation:

Ciprofloxacin is contraindicated in pregnancy and during breastfeeding.

Dosing and Administration:

Adults

In the absence of other prescriptions, the following dosing regimen should be followed.

Table 1. Recommended daily dose of the drug Ciprofloxacin solution for infusions in adults

Indications	Single dose for adults, taking into account the frequency of administration per day, mg (IV)
Respiratory tract infections (depending on the severity of the infection and the patient's condition)	from 400 mg twice a day to 400 mg 3 times a day
Infections of the genitourinary system:
- acute, uncomplicated	from 200 mg twice a day to 400 mg twice a day
- complicated	from 400 mg twice a day to 400 mg 3 times a day
- adnexitis, prostatitis, orchitis, epididymitis	from 400 mg twice a day to 400 mg 3 times a day
Diarrhea	400 mg twice daily
Other infections (see "Indications")	400 mg twice daily
Particularly serious, life-threatening, especially if available Pseudomonas spp., Staphylococcus spp. or Streptococcus spp., including: - pneumonia caused by Streptococcus spp.; - recurrent infections in cystic fibrosis of the lungs; - infection of bones and joints; - septicemia; - peritonitis	400 mg 3 times a day
Pulmonary form of anthrax (treatment and prevention)	400 mg twice a day (adults)

Children and teens

Table 2. The recommended daily dose of the drug Ciprofloxacin solution for infusions in children and adolescents

Indications

Single dose for children and adolescents, taking into account the frequency of administration per day, mg (IV)

Infections in cystic fibrosis

10 mg / kg body weight 3 times a day

(the maximum dose is 400 mg)

Pulmonary form of anthrax (postcontact)

10 mg / kg body weight 2 times a day

(the maximum dose is 400 mg)

Use in selected patient groups

Dosage regimen in elderly patients (over 65 years of age)

Elderly patients should be prescribed lower doses of ciprofloxacin, depending on the severity of the disease and the clearance of creatinine (see also information on patients with impaired hepatic and / or renal function).

Dosage regimen for pulmonary form of anthrax (treatment and prevention) for adults and children

See Table. 1 and 2. Treatment should be started immediately after suspected or confirmed infection.

The total duration of treatment with ciprofloxacin in pulmonary form of anthrax is 60 days.

The dosing regimen for violations of kidney or liver function in adults

Table 3. Recommended doses for patients with renal insufficiency

Creatinine clearance, ml / min / 1.73 m²	Creatinine serum, mg / 100 ml	Total daily dose Ciprofloxacin solution for infusion
from 30 to 60	from 1.4 to 1.9	maximum 800 mg
below 30	>2,0	maximum 400 mg

Dosing regimen for renal dysfunction in patients on hemodialysise

- with a clearance of creatinine from 30 to 60 ml / min / 1.73 m² or its concentration in plasma from 1.4 to 1.9 mg / 100 ml, the maximum dose of ciprofloxacin should be 800 mg / day;

- with creatinine clearance ≤30 ml / min / 1.73 m² (severe renal failure) or its plasma concentration ≥2 mg / 100 ml, the maximum dose of ciprofloxacin should be 400 mg / day on dialysis days after the procedure.

Dosing regimen in patients with renal failure with prolonged outpatient peritoneal dialysis

Ciprofloxacin is added to the dialysate (intraperitoneally): 50 mg of ciprofloxacin per liter of dialysate is administered 4 times a day every 6 hours.

Dosing regimen in patients with hepatic insufficiency

Correction of the dose is not required.

Dosing regimen in patients with impaired renal or hepatic function

- with a clearance of creatinine from 30 to 60 ml / min / 1.73 m² (moderate renal insufficiency) or at a creatinine concentration in the blood plasma from 1.4 to 1.9 mg / 100 ml, the maximum daily dose of ciprofloxacin should be 800 mg;

- with creatinine clearance ≤30 ml / min / 1.73 m² (severe renal failure) or at a creatinine concentration in the blood plasma ≥2 mg / 100 ml, the maximum daily dose of ciprofloxacin should be 400 mg.

Dosage regimen for violations of kidney or liver function in children

The dosage regimen in children with impaired renal and hepatic function has not been studied.

Mode of application

Preparation of the solution: before use, 1 bottle with concentrate for solution for infusion should be diluted with an adequate amount of the infusion solution: 0.9% solution of sodium chloride (NaCl), Ringer's solution, 5% and 10% dextrose solution with 10% fructose solution, containing 5% dextrose solution with 0.225% or 0.45% NaCl solution, to a minimum volume of 50 ml.

A solution of ciprofloxacin is administered as an intravenous infusion lasting at least 60 minutes. The infusion solution should be injected slowly into a large vein, which will prevent the development of complications at the site of infusion. The infusion solution can be administered alone or together with other compatible infusion solutions.

Compatibility with other solutions

The infusion solution of ciprofloxacin is compatible with 0.9% solution NaCl, Ringer's solution, 5% and 10% dextrose solution, 10% fructose solution, and 5% dextrose solution with 0.225 or 0.45% solution NaCl.

The solution obtained after mixing the ciprofloxacin solution with compatible infusion solutions should be used as soon as possible because of the sensitivity of the drug to light and to maintain the sterility of the solution.If compatibility with another infusion solution / drug is not confirmed, the infusion solution of ciprofloxacin should be administered separately. Visible signs of incompatibility are precipitation, clouding or discoloration of the solution. Incompatibility is observed with all solutions / preparations that are physically or chemically unstable at pH of the infusion solution of 3.9-4.5 (for example, penicillins, heparin solutions), and in particular with solutions that change the pH value to the alkaline side. The infusion solution of ciprofloxacin is photosensitive, so the vial should be removed from the box only before use. In case of direct sunlight, the guaranteed stability of the solution is 3 days. When storing the infusion solution of ciprofloxacin at low temperatures, a precipitate may form which dissolves at room temperature. Therefore, it is not recommended to store the infusion solution in the refrigerator and freeze.

Use only a clear, clear solution.

Duration of therapy

The duration of treatment depends on the severity, clinical course and cure of the disease.It is important to continue treatment for at least 3 days after the disappearance of fever or other clinical symptoms. Average duration of treatment:

Adults:

- 1 day with acute uncomplicated gonorrhea;

- up to 7 days with infections of the kidneys, urinary tract, abdominal organs;

- the entire neutropenia period in immunocompromised patients;

- no more than 2 months with osteomyelitis;

- from 7 to 14 days with other infections.

When infections, caused by Streptococcus spp., Due to the risk of late complications, treatment should last at least 10 days.

When infections caused by Chlamydia spp., treatment should also be continued for at least 10 days.

Children and teens:

- for treatment of complications of cystic fibrosis of the lungs caused by Pseudomonas aeruginosa (in patients from 5 to 17 years), the duration of therapy is 10-14 days.

Side effects:

The following adverse reactions were classified as follows: very often (≥ 10), often (≥1 / 100, <1/10) infrequently (≥1 / 1000 <1/100), rare (≥1 / 10 000 < 1/1000), very rarely (<10 000), the frequency is unknown.

Unwanted reactions, which were recorded only during post-marketing observations, whose frequency was not evaluated, are designated as "frequency unknown."

Hasto	Infrequently	Rarely	Rarely	Frequency unknown
INFECTIOUS AND PARASITARY DISEASES
	Fungal superinfection	Pseudomembranous colitis (in very rare cases - with possible fatal outcome)
FROM THE SIDE OF THE SYSTEM OF BLEEDING
	Eosinophilia	Leukopenia Anemia Neutropenia Leukocytosis Thrombocytopenia Thrombocythemia	Hemolytic anemia Agranulocytosis Pancytopenia (life threatening) Oppression bone marrow (life threatening)
FROM THE SIDE OF THE IMMUNE SYSTEM
		Allergic reactions Allergic edema / angioedema	Anaphylactic reactions Anaphylactic shock (life threatening) Whey disease
FROM THE SIDE OF EXCHANGE OF SUBSTANCES AND NUTRITION
	Decreased appetite and the amount of food	Hyperglycaemia Hypoglycaemia
MENTAL DISORDERS
	Psychomotor hyperactivity / agitation	Confusion and disorientation Anxiety Disturbance of dreams (nightmares) Depression (which can lead to self-damaging behavior, such as suicidal behavior / thoughts, as well as attempted suicide or suicide) Hallucinations	Psychotic reactions (which can lead to self-damaging behavior, such as suicidal behavior / thoughts,as well as attempted suicide or suicide)
FROM THE SIDE OF THE CENTRAL NERVOUS SYSTEM
	Headache Dizziness Sleep disturbance Disturbance of taste	Paresthesia and dysesthesia Hypesesia Tremor Convulsions (including epileptic seizures) Vertigo	Migraine Violation of coordination of movements Impaired smell Hyperesthesia Intracranial hypertension (benign)	Peripheral neuropathy and polyneuropathy
FROM THE PARTY OF THE ORGANIZATION
		Visual disturbances	Violation color perception
FROM THE SIDE OF THE HEARING BODY AND LABYRINTH DISTURBANCES
		Noise in ears Hearing Loss	Hearing Impairment
FROM THE HEART OF THE HEART
		Tachycardia		Interval lengthening QT Ventricular arrhythmias (including the "pirouette" type) *
FROM THE SIDE OF VESSELS
		Vasodilation Reduction of blood pressure Feeling of a "tide" of blood to the face	Vasculitis
FROM THE SIDE OF THE RESPIRATORY SYSTEM, BREAST CANCER AND MEDIUM ENVIRONMENT
		Disturbance of breathing (including bronchospasm)
FROM THE SIDE OF THE GASTROINTESTINAL TRACT
Nausea Diarrhea	Vomiting Abdominal pain Dyspepsia Flatulence		Pancreatitis
FROM THE LIVER'S side and the biliary tract
	Increased activity of "liver" transaminases Increased bilirubin concentration	Dysfunction of the liver Jaundice Hepatitis (non-infectious)	Necrosis of liver tissue (in extremely rare cases progressing to life-threatening liver failure)
FROM THE SIDE OF SKIN AND SUBCUTANEOUS TISSUE
	Rash Itching Hives	Photosensitivity Blistering	Petechia Multi-form erythema of small forms Nodal erythema Stevens-Johnson syndrome (malignant exudative erythema), including potentially life-threatening Lyell's syndrome (toxic epidermal necrolysis), including potentially life-threatening	Acute generalized pustular exanthema
FROM THE SIDE OF THE SKELETAL-MUSCULAR AND CONNECTING TISSUE
	Arthralgia	Myalgia Arthritis Increased muscle tone, muscle cramps	Muscle weakness Tendonitis Rupture of tendons (predominantly Achilles) Exacerbation symptoms myasthenia gravis
FROM THE SIDE OF THE KIDNEY AND URINARY OUTLOOK
	Impaired renal function	Renal failure, hematuria Crystalluria Tubulointerstitial nephritis
GENERAL DISTURBANCES AND VIOLATIONS IN THE SITE OF INTRODUCTION
Reactions at the site of administration	Pain syndrome nonspecific etiology General malaise Fever	Edema Sweating (hyperhidrosis)	Violation of gait
LABORATORY INDICES
	Increased activity of alkaline phosphatase in the blood	Change in the concentration of prothrombin Increase of amylase activity		An increase in the international normalized relationship (INR) (in patients receiving vitamin K antagonists)

* More common in patients who are predisposed to develop prolongation of the QT interval (see section "Special instructions").

The frequency of development of the following adverse reactions with intravenous administration and with the use of stepwise therapy with ciprofloxacin (with intravenous administration of the drug with subsequent ingestion) is higher than with oral administration:

Often	Vomiting, increased activity of "liver" transaminases, rash
Infrequently	Thrombocytopenia, thrombocytopenia, confusion and disorientation, hallucinations, paresthesia and dysesthesia, convulsions, vertigo, visual impairment, hearing loss, tachycardia, vasodilation, lowering of blood pressure, reversible liver function disorders, jaundice, kidney failure, swelling
Rarely	Pancytopenia, bone marrow depression, anaphylactic shock, psychotic reactions, migraine,impaired smell, hearing impairment, vasculitis, pancreatitis, necrosis of liver tissue, petechiae, rupture of tendons

Children

Children often reported on the development of arthropathy.

Overdose:

Symptoms: nausea, vomiting, confusion, mental agitation.

Treatment: the specific antidote is unknown. It is necessary to carefully monitor the patient's condition, conduct symptomatic therapy, and ensure sufficient fluid intake. In order to prevent the development of crystalluria, it is recommended to monitor renal function, including the acidity (pH) of urine. With the help of hemo- or peritoneal dialysis, only a small amount (less than 10%) of the drug can be excreted.

Interaction:

The drugs that cause lengthening are interesting QT

Caution should be exercised with the simultaneous use of ciprofloxacin, as well as other fluoroquinolones, in patients receiving medications that cause lengthening of the interval QT (for example, antiarrhythmic drugs of the class IA or class III, tricyclic antidepressants, macrolides, antipsychotics) (see section "Special instructions").

Theophylline

Simultaneous use of ciprofloxacin and preparations containing theophylline, can cause an undesirable increase in the concentration of theophylline in the blood plasma and, accordingly, the occurrence of theophylline-induced adverse events; in very rare cases, these side effects can be life threatening to the patient. If the simultaneous use of these two drugs is inevitable, it is recommended that continuous monitoring of the concentration of theophylline in the blood plasma and, if necessary, reduce the dose of theophylline.

Other xanthine derivatives

Simultaneous use of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline) may lead to an increase in the concentration of xanthine derivatives in the blood serum.

Phenytoin

With the simultaneous use of ciprofloxacin and phenytoin, there was a change (increase or decrease) in the content of phenytoin in the blood plasma. In order to avoid the occurrence of convulsions associated with a decrease in the concentration of phenytoin, and also to prevent undesirable phenomena associated with a phenytoin overdose when ciprofloxacin is discontinued, it is recommended to monitor phenytoin therapy in patients,taking both drugs, including the determination of the content of phenytoin in the blood plasma during the entire period of simultaneous application of both drugs and for a short time after the completion of the combination therapy.

Nonsteroidal anti-inflammatory drugs

The combination of very high doses of quinolones (DNA-gyrase inhibitors) and some non-steroidal anti-inflammatory drugs (excluding acetylsalicylic acid) can provoke convulsions.

Cyclosporin

With the simultaneous use of ciprofloxacin and drugs containing ciclosporin, a transient transient increase in the concentration of creatinine in the blood plasma was observed. In such cases it is necessary to determine the concentration of creatinine in the blood twice a week.

Oral hypoglycemic agents

With the simultaneous use of ciprofloxacin and oral hypoglycemic agents, mainly sulfonylureas (for example, glibenclamide, glimepiride), the development of hypoglycemia may be due to an increase in the effect of oral hypoglycemic agents (see section "Side effect").

Probenecid

Probenecid slows the rate of excretion of ciprofloxacin by the kidneys.Simultaneous use of ciprofloxacin and preparations containing probenecid, leads to an increase in the concentration of ciprofloxacin in the blood serum.

Methotrexate

With the simultaneous use of methotrexate and ciprofloxacin, the renal tubular transport of methotrexate may be slowed, which may be accompanied by an increase in the concentration of methotrexate in the blood plasma. This may increase the likelihood of side effects of methotrexate. In this regard, for patients receiving simultaneously methotrexate and ciprofloxacin, careful monitoring must be established.

Tizanidine

As a result of a clinical study involving healthy volunteers with simultaneous use of ciprofloxacin and drugs containing tizanidine, an increase in the concentration of tizanidine in blood plasma: an increase in C_mOh in 7 times (from 4 to 21 times), the increase in the indicator AUC in 10 times (from 6 to 24 times). With an increase in the concentration of tizanidine in the blood serum, hypotensive (lowering blood pressure) and sedative (drowsiness, lethargy) are associated with side effects. Thus, the simultaneous use of ciprofloxacin and preparations containing tizanidine, is contraindicated.

Duloxetine

During clinical trials, it was shown that the simultaneous use of duloxetine and potent inhibitors of isoenzyme CYP450 1A2 (such as fluvoxamine) can lead to an increase AUC and C_mOh duloxetine. Despite the lack of clinical data on the possible interaction with ciprofloxacin, it is possible to foresee the likelihood of such interaction with the simultaneous use of ciprofloxacin and duloxetine.

Ropinirole

The simultaneous use of ropinirole and ciprofloxacin, a moderate isoenzyme inhibitor CYP450 1A2, leads to an increase in C_mOh and AUC ropinirole by 60% and 84%, respectively. It is necessary to monitor the side effects of ropinirole during its combined use with ciprofloxacin and for a short time after completion of the combination therapy.

Lidocaine

In a study involving healthy volunteers, it was found that the simultaneous use of drugs containing lidocaine, and ciprofloxacin, a moderate isoenzyme inhibitor CYP450 1A2, leads to a decrease in clearance of lidocaine by 22% with its intravenous administration. Despite the good tolerability of lidocaine, simultaneous use with ciprofloxacin may increase the side effects due to interaction.

Clozapine

With the simultaneous use of clozapine and ciprofloxacin at a dose of 250 mg for 7 days, an increase in serum concentrations of clozapine and N-desmethylclozapine by 29 and 31%, respectively. It is necessary to monitor the patient's condition and, if necessary, adjust the dosage regimen of clozapine during its simultaneous use with ciprofloxacin and for a short time after completion of the combination therapy.

Sildenafil

With the simultaneous use in healthy volunteers, ciprofloxacin at a dose of 500 mg and sildenafil at a dose of 50 mg there was an increase FROM_m_Oh and the area under the sildenafil curve is 2 times. In this regard, the application of this combination is possible only after the evaluation of the benefit / risk ratio.

Antagonists of vitamin K

The combined use of ciprofloxacin and vitamin K antagonists (eg, warfarin, acenocoumarol, fenprocumone, fluindone) may lead to an increase in their anticoagulant effect. The magnitude of this effect may vary depending on the concomitant infections, age and general condition of the patient, so it is difficult to assess the effect of ciprofloxacin on an increase in INR.It is often enough to monitor INR during joint use of ciprofloxacin and vitamin K antagonists, and also for a short time after the completion of combination therapy.

Special instructions:

Severe infections, staphylococcal infections and infections, conditional gram-positive and anaerobic bacteria

In the treatment of severe infections, staphylococcal infections and infections caused by anaerobic bacteria, ciprofloxacin should be used in combination with appropriate antibacterial agents.

Infections, conditional Streptococcus pneumoniae

Ciprofloxacin is not recommended for the treatment of infections caused by Streptococcus pneumoniae, due to its limited effectiveness against the pathogen.

Infections of the reproductive tract

In genital infections presumably caused by strains Neisseria gonorrhoeae, resistant to fluoroquinolones, should take into account information on local resistance to ciprofloxacin and confirm the sensitivity of the causative agent in laboratory tests.

Heart Disease

Ciprofloxacin influences lengthening of the interval QT (see section "Side effect").Given that women are characterized by a large average duration of the interval QT compared with men, they are more sensitive to drugs that cause lengthening of the interval QT. In elderly patients there is also an increased sensitivity to the action of drugs that cause lengthening of the interval QT. Therefore, you should use caution ciprofloxacin in combination with drugs that extend the interval QT (for example, antiarrhythmic drugs classes IA and III, tricyclic antidepressants, macrolides, and antipsychotics) (see "Interactions with Other Drugs"), or in patients at increased risk of lengthening the interval QT or the development of piruet-type arrhythmias (for example, with congenital lengthening interval syndrome QT, unadjusted electrolyte imbalance, such as hypokalemia or hypomagnesemia, as well as heart diseases such as heart failure, myocardial infarction, bradycardia).

Use in children

It was found that ciprofloxacin, like other drugs of this class, causes arthropathy of large joints in animals.

When analyzing the currently available data on the safety of ciprofloxacin in children under 18 years of age, most of whom have cystic fibrosis of the lung, there is no association between cartilage damage and joints with drug administration. It is not recommended to use ciprofloxacin in children for the treatment of other diseases, except for complications of cystic fibrosis of the lungs (in children from 5 to 17 years) associated with Pseudomonas aeruginosa, as well as for the treatment and prevention of the pulmonary form of anthrax (after suspected or proven infection Bacillus anthracis).

Hypersensitivity

Sometimes, after taking the first dose of ciprofloxacin, hypersensitivity to the drug may develop, including allergic reactions, which should be reported immediately to the treating physician (see the "Side effect" section). In rare cases, after the first application, anaphylactic reactions may occur up to anaphylactic shock. In these cases, the use of ciprofloxacin should be stopped immediately and appropriate treatment should be given.

Gastrointestinal tract

If a severe and prolonged diarrhea occurs during or after treatment with ciprofloxacin, the diagnosis of pseudomembranous colitis should be excluded,which requires immediate withdrawal of the drug and the appointment of appropriate treatment (vancomycin inside in a dose of 250 mg 4 times a day) (see section "Side effect").

Contraindicated in the use of drugs that suppress the intestinal peristalsis.

Hepatobiliary system

When ciprofloxacin was used, cases of liver necrosis and life-threatening liver failure were noted. If you have the following signs of liver disease, such as anorexia, jaundice, darkening of the urine, itching, soreness of the abdominal region, taking ciprofloxacin should be discontinued (see section "Side effect").

In patients receiving ciprofloxacin and those suffering liver disease, there may be a temporary increase in activity of "liver" transaminases, alkaline phosphatase or cholestatic jaundice (see section "Side effect").

Musculoskeletal system

Patients with severe myasthenia gravis should be applied ciprofloxacin with caution, as possible exacerbation of symptoms.

When taking ciprofloxacin, there may be cases of tendinitis and rupture of tendons (mainly Achilles tendon), sometimes bilateral, within the first 48 hours after the initiation of therapy.Inflammation and rupture of the tendon can occur even a few months after cessation of ciprofloxacin treatment. In elderly patients and patients with diseases of tendons treated simultaneously with corticosteroids, there is an increased risk of tendonopathy.

At the first signs of tendonitis (painful swelling in the joint area, inflammation), the use of ciprofloxacin should be discontinued, exclude physical activity, as there is a risk of rupture of the tendon, and consult a doctor. Ciprofloxacin should be used with caution in patients with a history of indications of tendon diseases associated with the administration of quinolones.

Nervous system

Ciprofloxacin, like other fluoroquinolones, can provoke convulsions and reduce the threshold of convulsive readiness. Patients with epilepsy and advanced CNS diseases (eg, lowering the threshold of convulsive readiness, convulsive seizures in the history, cerebrovascular disorders, organic brain lesions or stroke) due to the threat of developing side effects from the CNS ciprofloxacin should be used only in those cases when the expected clinical effect exceeds the possible risk of side effects of the drug.

When ciprofloxacin was used, cases of development of epileptic status were reported (see section "Side effect"). In case of seizures, the drug should be discontinued. Mental reactions may occur even after the first use of fluoroquinolones, including ciprofloxacin. In rare cases, depression or psychotic reactions can progress to suicidal thoughts and self-damaging behavior, such as suicide attempts, including those committed (see "Side effect"). If a patient develops one of these reactions, stop taking ciprofloxacin and tell the doctor about it.

In patients taking fluoroquinolones, including ciprofloxacin, there were cases of sensory or sensorimotor polyneuropathy, hypesthesia, dysesthesia, or weakness. If symptoms such as pain, burning, tingling, numbness, weakness occur, patients should inform the doctor about this before continuing the use of the drug.

Skin covers

When taking ciprofloxacin, a photosensitization reaction may occur, so patients should avoid contact with direct sunlight and ultraviolet light. Treatment should be discontinued if symptoms of photosensitivity are observed (for example, skin changes resemble sunburn) (see section "Side effect").

Cytochrome P450

It is known that ciprofloxacin is a moderate inhibitor of isoenzyme CYP 450 1A2. Caution should be exercised with the simultaneous use of ciprofloxacin and drugs metabolized by these isoenzymes, such as theophylline, methylxanthine, caffeine, duloxetine, ropinirole, clozapine, olanzapine and others, since an increase in the concentration of these drugs in the blood serum, due to the inhibition of their metabolism by ciprofloxacin, can cause specific undesirable reactions.

Local Reactions

With intravenous administration of ciprofloxacin, a local inflammatory reaction may occur at the site of the drug (swelling, pain). This reaction is more common if the infusion time is 30 minutes or less.The reaction quickly passes after the end of the infusion and is not a contraindication for the subsequent administration of the drug, unless its course becomes complicated.

To avoid the development of crystalluria, exceeding the recommended daily dose is inadmissible, adequate fluid intake and maintenance of acid urine reaction are also necessary. With simultaneous intravenous administration of ciprofloxacin and preparations for general anesthesia from the group of barbituric acid derivatives, continuous monitoring of the heart rate, blood pressure, and electrocardiogram is necessary. In vitro ciprofloxacin may interfere with bacteriological research Mycobacterium tuberculosis, suppressing its growth, which can lead to false-negative results in the diagnosis of this pathogen in patients taking ciprofloxacin.

Content NaCl

Consider the content NaCl in the solution of ciprofloxacin in the treatment of patients who have limited sodium intake (heart failure, kidney failure, nephrotic syndrome).

Effect on the ability to drive transp. cf. and fur:

During the treatment period, care must be taken when driving vehicles and mechanisms, as well as when engaging in other potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions. If unwanted reactions from the nervous system develop (for example, dizziness, convulsions), one should refrain from driving and practicing other activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Concentrate for solution for infusion, 10 mg / ml.

Packaging:

For 10 ml of the drug in flasks of colorless glass, hermetically sealed with rubber stoppers and crimped with aluminum or combined caps.

5 bottles along with the instructions for use are placed in a pack of cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Do not freeze.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003470

Date of registration:26.02.2016

Expiration Date:26.02.2021

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

R-PHARM, JSC Russia

Representation: & nbspR-PHARM, JSC R-PHARM, JSC Russia

Information update date: & nbsp29.07.2016

Illustrated instructions

Instructions

Ciprofloxacin (Ciprofloxacin)